头孢曲松游离浓度的测定及在预测肺组织浓度中的应用

doi:10.5246/jcps.2021.07.046

摘要/Abstract

摘要：

本研究的目的是以中空纤维超滤(HFCF-UF)技术为基础结合高效液相色谱法(HPLC), 建立一个测定血浆中头孢曲松(CEF)游离浓度, 以及预测肺组织游离头孢曲松浓度的方法。该方法只需短时间的离心后取超滤液, 无需其他处理即可直接注入HPLC进行分析。对该方法的特异性、线性、精密度及稳定性进行了验证, 在最优条件下, 绝对回收率大于92.5%, 日内和日间精密度的RSD小于3.6%。此外, 还考虑了分析物与超滤膜之间的非特异性吸附(NSB)。该方法成功地应用于大鼠血浆和肺组织中游离头孢曲松浓度的分析。肺组织中游离头孢曲松浓度可通过线性公式进行预测C_fl = C_fp (0.342x – 0.0129) (x: time)。该方法为临床治疗药物监测(TDM)中头孢曲松游离浓度的测定提供了一个参考依据。

关键词: 头孢曲松, 游离药物浓度, 中空纤维离心超滤法, 药动学

Abstract:

The purpose of this study was to establish a method for determining the free concentration of ceftriaxone based on hollow fiber centrifugal ultrafiltration (HFCF-UF) technology in combination with high-performance liquid chromatography (HPLC) for free pharmacokinetic studies and the prediction of ceftriaxone concentrations in lung tissue. This method only required centrifugation for a short time, and the filtrate could be injected directly for HPLC analysis without further treatment. The specificity, linearity, precision and stability of this method were validated for quantification of free ceftriaxone. Under the optimized conditions, the absolute recoveries were more than 92.5%. The intraday and interday precision RSDs were less than 3.6%. Additionally, nonspecific adsorption (NSB) between the analyte and the ultrafiltration membrane was considered. This method was successfully applied to the analysis of the free ceftriaxone concentration in rat plasma and lung tissue. The free ceftriaxone concentration of lung tissue could be predicted by using the linear formula C_fl = C_fp (0.342x – 0.0129) (x: time). This method also provides a reliable alternative for accurate monitoring of the free ceftriaxone concentration in therapeutic drug monitoring (TDM).

Key words: Ceftriaxone, Free tissue concentration, Hollow fiber centrifugal ultrafiltration, Pharmacokinetics

Supporting:

李亚男, 郭雪, 袁叶, 董维冲, 杨秀岭. 头孢曲松游离浓度的测定及在预测肺组织浓度中的应用[J]. 中国药学(英文版), 2021, 30(7): 578-589.

Yanan Li, Xue Guo, Ye Yuan, Weichong Dong, Xiuling Yang. Determination of free ceftriaxone concentration and its application in predicting lung tissue concentration[J]. Journal of Chinese Pharmaceutical Sciences, 2021, 30(7): 578-589.

图/表 14

Table 1. Linear ranges and tested concentrations of ceftriaxone.

Figure 1. HFCF-UF device.

Figure 2. HPLC chromatograms of ceftriaxone for the analysis of free plasma concentration: (A) 10. 00 μg/mL of ceftriaxone standard solution; (B) Blank plasma ultrafiltrate; (C) Blank plasma ultrafiltrate spiked with ceftriaxone standard solution (10.0 μg/mL); (D) Plasma sample after drug administration; 1 Represent the peak of ceftriaxone.

Figure 3. HPLC chromatograms of ceftriaxone for the analysis of free lung tissue concentration: (A) 8. 00 μg/mL of ceftriaxone standard solution; (B) Blank lung tissue ultrafiltrate; (C) Lung sample spiked with ceftriaxone standard solution; (D) Lung sample after drug administration; 1 Represent the peak of ceftriaxone.

Table 2. Linear ranges, LODs and LOQs of free ceftriaxone analysis in plasma and lung tissue.

Table 3. Results of recovery and precision tests of free ceftriaxone.

Table 4. The stability of ceftriaxone in plasma under various conditions (n = 5).

Table 5. The stability of ceftriaxone in lung tissue under different conditions (n = 5).

Table 6. The free plasma ceftriaxone concentration in rats at different time (n = 20).

Figure 4. Average plasma free concentration-time curve of ceftriaxone in rats.

Table 7. PK parameters of free ceftriaxone (mean ± SD) in rats after receiving ceftriaxone.

Table 8. Free ceftriaxone concentration in plasma and lung tissue at different time.

Figure 5. Ratio of free concentration in lung tissue to plasma in rats.

Table 9. Results of analyte recovery with four kinds of hollow fibers.

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